The Molecular Functioning of HDAC:co-repressor complexes. (360G-Wellcome-100237_Z_12_Z)

Histone deacetylases (HDACs) are increasingly recognised as important targets for the treatment of cancer and other diseases including Alzheimer's. They are essential enzymes required for human development & homeostasis. HDACs 1-3 serve as the catalytic subunits in several large transcriptional co-repressor complexes that are recruited to chromatin by repressive transcription factors. These complexes function by removing acetyl groups from histones resulting in condensation of chromatin and gen e silencing. Our research is concerned with elucidating the fundamental mechanisms through which HDACs 1-3 are regulated and how they target chromatin. Our recent structure of the HDAC3 co-repressor complex identified the small signalling molecule inositol tetraphosphate (IP4) as an essential co-factor (Nature 2012, 481, 335). The breakthrough realisation that IP4 acts as an epigenetic regulator suggests a completely new and unexpected mechanism for the regulation of gene repression. More rece ntly still, we have determined the structure of HDAC1 bound to the Metastases Associated Protein co-repressor (unpublished). This structure not only reveals the basis for the specific assembly of HDACs into their cognate complexes, but also reveals how the complex is targeted to chromatin. We propose to address the major outstanding questions concerning the biological role and mechanisms of action of histone deacetylase complexes: (i) to determine the structures of the four HDAC1 and HDAC3 hol o-complexes, defining the specificity of assembly and their role in determining target gene and substrate specificity (ii) to understand the biological role of IP4 in regulating HDAC complexes (iii) to explore potential therapeutic targeting of HDAC:co-repressor complexes by both small molecules and interfering peptides